rs146545930

Variant names:

• chr14-90397063-C-T
• rs146545930
• NM_006888.6:c.-168C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-90397063-C-T
• chr14-90397063-C-A
• chr14-90397063-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006888.6(CALM1):​c.-168C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 664,332 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (23 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (13 hom.)
• Consequence: CALM1 NM_006888.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.728
• Publications: 1 publications found

Genes affected

CALM1 (HGNC:1442): (calmodulin 1) This gene encodes one of three calmodulin proteins which are members of the EF-hand calcium-binding protein family. Calcium-induced activation of calmodulin regulates and modulates the function of cardiac ion channels. Two pseudogenes have been identified on chromosome 7 and X. Multiple transcript variants encoding different isoforms have been found for this gene.A missense mutation in the CALM1 gene has been associated with ventricular tachycardia.[provided by RefSeq, May 2020]

CALM1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• catecholaminergic polymorphic ventricular tachycardia 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 14-90397063-C-T is Benign according to our data. Variant chr14-90397063-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 679116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00871 (1326/152218) while in subpopulation AFR AF = 0.0291 (1211/41556). AF 95% confidence interval is 0.0278. There are 23 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1326 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006888.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	NM_006888.6	MANE Select	c.-168C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_008819.1	P0DP23
	CALM1	NM_006888.6	MANE Select	c.-168C>T		5_prime_UTR	Exon 1 of 6	NP_008819.1	P0DP23
	CALM1	NM_001363669.2		c.-106+405C>T		intron	N/A	NP_001350598.1	Q96HY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	ENST00000356978.9	TSL:1 MANE Select	c.-168C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000349467.4	P0DP23
	CALM1	ENST00000356978.9	TSL:1 MANE Select	c.-168C>T		5_prime_UTR	Exon 1 of 6	ENSP00000349467.4	P0DP23
	CALM1	ENST00000971957.1		c.-168C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000642016.1

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1323 AN: 152100 Hom.: 23 Cov.: 34

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00141 AC: 724 AN: 512114 Hom.: 13 Cov.: 6 AF XY: 0.00119 AC XY: 327 AN XY: 273826

African (AFR) AF: 0.0317 AC: 422 AN: 13308

American (AMR) AF: 0.00249 AC: 58 AN: 23278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15346

East Asian (EAS) AF: 0.0000318 AC: 1 AN: 31492

South Asian (SAS) AF: 0.000136 AC: 7 AN: 51568

European-Finnish (FIN) AF: 0.000300 AC: 10 AN: 33298

Middle Eastern (MID) AF: 0.00560 AC: 14 AN: 2502

European-Non Finnish (NFE) AF: 0.000435 AC: 136 AN: 312832

Other (OTH) AF: 0.00267 AC: 76 AN: 28490

GnomAD4 genome AF: 0.00871 AC: 1326 AN: 152218 Hom.: 23 Cov.: 34 AF XY: 0.00800 AC XY: 595 AN XY: 74418

African (AFR) AF: 0.0291 AC: 1211 AN: 41556

American (AMR) AF: 0.00484 AC: 74 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67986

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0101

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.91
PhyloP100		0.73
PromoterAI		0.051	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146545930; hg19: chr14-90863407;